Live Attenuated Oral Anthrax Vaccine

描述（由申请人提供）：疫苗是一种经过验证的有效方法，可确保在生物恐怖袭击之前或之后立即对大量人群进行广泛保护。我们的目标是解决目前由生物恐怖主义威胁引起的两个重大问题：1)需要一种简便的大规模疫苗接种方法；2)目前的炭疽疫苗（NIAID“A类”剂）的缺点，需要针头和卫生专业人员进行注射，需要延长疫苗接种时间表（18个月6次），以及对不良反应的担忧。为了应对这一挑战，我们利用现有口服伤寒沙门氏菌Ty21a活疫苗的广泛安全记录，以其为载体，开发了一种稳定表达rPA的口服活疫苗载体。我们假设Ty21a是一种合适的疫苗载体，可以稳定表达rPA基因在低拷贝数质粒上。此外，我们假设这种疫苗可以配制成安全、稳定和高度免疫原性的疫苗，并且可以很容易地口服给药。目前的建议旨在完成必要的最后开发步骤（例如从载体质粒中去除抗生素抗性基因），并在构建遗传种子库和小规模（5-10升）生产和冻干之前对候选物进行全面表征（遗传和微生物学）。最后，将在小鼠炭疽病模型中研究候选药物的遗传稳定性、安全性、免疫原性和有效性。这一I期SBIR的成功完成将为在II期提案中开发口服炭疽疫苗以及针对多种其他感染因子的口服疫苗的平台技术奠定基础。

DESCRIPTION (provided by applicant): Vaccines are a proven and effective approach for assuring widespread protection of large populations prior to or immediately following a bioterrorism attack. Our goal is to address two significant problems currently raised by bioterrorism threats: 1) the need for an easy method of mass vaccination and 2) the shortcomings of the current anthrax vaccine (NIAID "category A" agent) which requires needles and health professionals for administration, an extended vaccination schedule for protection (6 doses over 18 months) and the concern over adverse effects. To address this challenge, we have exploited the extensive safety record of the existing live, oral Salmonella Typhi Ty21a vaccine by utilizing it as a vector to develop a live oral vaccine carrier stably expressing rPA. We hypothesize that Ty21a is a suitable vaccine carrier for the stable expression of the rPA gene harbored on a low copy number plasmid. Further, we hypothesize that this vaccine can be formulated so that it will be safe, stable, and highly immunogenic and can be easily administered orally. The current proposal is aimed at completing the necessary final development steps (e.g. removal of antibiotic resistance gene from vector plasmid) and full characterization (genetic and microbiological) of the candidate prior to constructing a genetic seed bank and small-scale (5-10 liter) manufacture and lyophilization. Finally, the candidate will be studied for genetic stability, safety, immunogenicity and efficacy in a mouse model of anthrax disease. Successful completion of this Phase I SBIR will provide the foundation for development of an oral anthrax vaccine in a Phase II proposal, and for a platform technology for oral vaccines against multiple other infectious agents. PUBLIC HEALTH RELEVANCE: Anthrax bacteria produce spores that can be processed to become easily airborne. Vaccines are a proven and effective approach for assuring widespread protection of large populations prior to or immediately following a bioterrorism attack. Our goal is to address two significant problems currently raised by bioterrorism threats: 1) the need for an easy method of mass vaccination and 2) the shortcomings of the current anthrax vaccine (NIAID "category A" agent) which requires needles and health professionals for administration, an extended vaccination schedule for protection (6 doses over 18 months) and the concern over adverse effects. Further, we hypothesize that this vaccine can be formulated so that it will be safe, stable, and highly immunogenic and ultimately can be easily administered orally.